Aging and reproduction are central aspects of life history. We have found that in C. elegans, signals from the reproductive system regulate lifespan. When the germ cells are removed, lifespan is increased approximately sixty percent. This regulation may be evolutionarily conserved, as germline-stem cell removal in flies also extends lifespan. It is possible that the control of aging by reproductive tissues provides a way for the animal to coordinate its rate of aging with its timing of reproduction. In C. elegans, signals from the reproductive system affect lifespan by controlling the FOXO-family transcription factor DAF-16. DAF-16/FOXO-dependent transcription is known to be stimulated when the level of insulin/IGF-1 hormone signaling is reduced, but the genes needed to stimulate DAF-16's activity when the germline is removed are not needed to stimulate DAF-16 when insulin/IGF-1 signaling is reduced. Therefore, in essence, we are studying a new signaling pathway that conveys information about reproductive status to evolutionarily-conserved, core longevity mechanisms. We have learned that germ-cell loss triggers a molecular response in another tissue, the intestine, which includes the nuclear localization of DAF-16/FOXO and increased expression of gos-1, which encodes another transcription factor. (In C. elegans, the intestine behaves as the entire endoderm, including the adipose tissue.). Both DAF-16 and GOS-1 are required for lifespan extension, and both are required for new patterns of gene expression in animals that lack germ cells. We have identified several genes, including components of a Wnt signaling pathway, that allow the reproductive system to control DAF-16 and GOS-1, and we have developed powerful tools for their analysis. Using these tools, we will ask whether a Wnt signal conveys information about the reproductive system to the intestine, and we will ask what events occur in the intestine to cause DAF-16 and GOS-1 to stimulate new patterns of gene expression. This is exciting, because understanding this system well at the molecular level may suggest ways to artificially activate conserved longevity mechanisms in humans, with great health and longevity benefits. PUBLIC HEALTH RELEVANCE: Mutations that increase lifespan also confer resistance to age-related disease. We have found that the reproductive system of C. elegans, a simple roundworm, influences lifespan by signaling to core, evolutionarily-conserved longevity pathways. We have identified new genes that convey information from the reproductive tissues to these conserved pathways. We propose to learn how signals from the reproductive system influence lifespan, in hopes of finding new ways to increase youthfulness and health, and to combat age-related disease, in humans.